Birth asphyxia is a major cause of hypoxic-ischemic (HI) cerebral injury leading to lifelong disability. In order to understand mechanisms of HI brain injury, the proposed research focuses on a complement- mediated inflammatory pathway which has been implicated in post-ischemic neuronal damage. C1q, the initial component of the classical complement (C) pathway, appears to participate in HI cerebral damage through direct neuronal injury and indirectly through inflammatory amplification. Preliminary data indicate that C1q-gene deleted (-/-) neonatal mice are strikingly protected against Hl-insult, which implies a critical role for both this initial trigger of C activation and for the classical C cascade itself as mediators of post-ischemic cerebral damage. In concordance with these data, significantly greater deposition of C1q, C3 and C3-split products, and C9 in ischemic brain was associated with greater extent of cerebral damage in WT-mice compared to C1q-/- counterparts. In dissecting constituents of this pathway, we have further shown that neuroprotection is more robust in C1q-/- than C3-/- mice, leading us to hypothesize that C1q mediates neuronal injury not only via terminal activation of C, but also by a more proximal mechanism independent of the requirement for C3-cleavage. The two Specific Aims of this proposal are (1) To determine whether neuronal deposition of C1q results in membrane attack complex (MAC)-dependent neuronal injury following Hl-insult, and (2) To determine whether C1q, independent of the terminal C activation, exacerbates mitochondrial dysfunction and neuronal death following Hl-insult. For these experiments, molecular, genetic, and pharmacologic approaches will be undertaken to elucidate Clq-mediated mechanisms of Hl-neurodamage and determine a novel therapeutic target for perinatal neuroprotection. These experiments will establish mechanisms for the injurious role of a primitive immune defense system in brain injury caused by HI, thereby enabling development of new therapeutic targets to protect the brain which could minimize lifelong disability. [unreadable] [unreadable] [unreadable]